Cytotoxic Fractions from Extracts and -Coumaric Acid as MAPK Inhibitors.

Preliminary bioassay-guided fractionation was performed to identify cytotoxic compounds from , a plant that is used in Mexican ethnomedicine. Organic and aqueous extracts were prepared from 's leaves and evaluated against two cancer cell lines. The CHCl/MeOH (1:1) active extract was fractionated, and the resulting fractions were assayed against prostate adenocarcinoma PC3 and breast adenocarcinoma MCF7 cell lines. Active fraction was further analyzed by high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry analysis to identify its active constituents. Among the compounds that were responsible for the cytotoxic effects of this fraction were flavonoids, phenolic acids, and aromatic compounds, of which -coumaric acid (-CA) and its derivatives were abundant. To understand the mechanisms that underlie -CA cytotoxicity, a microarray assay was performed on PC3 cells that were treated or not with this compound. The results showed that mitogen-activated protein kinases (MAPKs) that regulate many cancer-related pathways were targeted by -CA, which could be related to the reported effects of reactive oxygen species (ROS). A molecular docking study of -CA showed that this phenolic acid targeted these protein active sites (MAPK8 and Serine/Threonine protein kinase 3) at the same binding site as their inhibitors. Thus, we hypothesize that -CA produces ROS, directly affects the MAPK signaling pathway, and consequently causes apoptosis, among other effects. Additionally, -CA could be used as a platform for the design of new MAPK inhibitors and re-sensitizing agents for resistant cancers.